This proposal seeks support to study two classes of drugs, iron chelating agents, and xanthine oxidase inhibitors, given during reperfusion of ischemic myocardium to prevent evolution of tissue damage during reperfusion. The relevant biochemical hypothesis states that free iron, liberated from bound intracellular stores during or after ischemia, combines with superoxide ions and hydrogen peroxide during reperfusion to catalyze initiation of free radical reactions that cause tissue damage. Chelation of intracellular iron by deferoxamine (a commercially available drug, that distributes to the intracellular space and has a high affinity for iron ions) and inhibition of superoxide production by xanthine oxidase may prevent such reactions. In related research we have developed a rat model of total circulatory arrest and resuscitation in which cardiac arrest of 7 min duration is followed by external CPR. Intravenous deferoxamine or allopurinol was given after restoration of the heartbeat, and long term survival was the endpoint. Ten day survival was 64% in the deferoxamine treated group vs. 36% survival in the control group, a statistically significant difference (X2 = 3.92,df = 1,p lesser 0.05). Ten days survival was 64% in the allopurinol treated rats vs. 27% in a concomitant control group (X2 = 5.78,df = 1,p lesser 0.05). Thus, both drugs prevented late deaths when given at the onset of reperfusion. We now propose to study myocardial reperfusion in particular using a convenient and efficient isolated heart model. The research will generate dose-response curves for allopurinol and for deferoxamine in which dose is measured in terms of concentration in perfusate during reperfusion and response is measured in terms of the following end-points as a function of time; CK and LDH release into perfusate, contractile function and Starling characteristic, tissue contents of products of lipid peroxidation (malondialdehyde and conjugated dienes), and electron microscopic abnormalities in endothelium and cardiomyocytes. The results may pave the way toward use of these safe and available agents as adjuncts to clinical thrombolytic therapy for acute myocardial infarction.